Associate Professor of Medicine (Cardiovascular Medicine) at the Stanford University Medical Center

Medicine - Cardiovascular Medicine

Bio

Bio

Phillip C. Yang is an Associate Professor of Medicine (Cardiovascular Medicine) at the Stanford University School of Medicine. He directs the Cardiovascular Stem Cell Laboratory (Yang Lab) and Stanford Cardiothoracic MRI Program. Dr. Yang received degrees from Stanford University and Yale University School of Medicine, and completed post-graduate training at UCLA and Stanford University Medical Centers. Dr. Yang is a physician-scientist whose research interest focuses on clinical translation of the fundamental molecular and cellular processes of myocardial regeneration. His research employs novel in vivo multi-modality molecular and cellular imaging technology to translate the basic innovation in stem cell biology. Dr. Yang is currently a PI on the NIH/NHLBI funded CCTRN UM1 grant, which is designed to conduct multi-center clinical trial on novel stem cell therapy. In addition, he is a PI on 3 NIH research grants, 1 CIRM grant, and leads 3 stem cell clinical trials. He hopes to pioneer the Cardiovascular Regeneration Program at Stanford. Dr. Yang has been the recipient of several prestigious awards including NIH Career Development Award, NIH Career Enhancement Award in Stem Cell Biology, and NIH Patient Oriented Research.

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Research & Scholarship

Current Research and Scholarly Interests

The emergence of regenerative medicine created a paradigm shift in how we approach cardiovascular diseases. This innovation has required a careful evaluation of the interaction between the recipient tissue and stem cells at a fundamental cellular and molecular level. Dr. Yang's laboratory is advancing cellular and molecular imaging technology to characterize the injured myocardium as a biological niche for stem cells and to discover novel cardiovascular stem cells and their derivatives to cure heart failure.

As a physician-scientist, Dr. Yang's research focuses on translational effort of cardiovascular regeneration. His laboratory combines stem cell biology with novel imaging technology to advance clinical implementation of induced pluripotent stem cells (iPSCs) and their derivatives. High sensitivity and exquisite resolution enable robust evaluation of stem cell survival, proliferation, and regional cardiac function. Regenerative medicine will trigger a paradigm shift and his research provides a requisite validation of the role of iPSCs and their molecular derivatives. He is pioneering the Cardiovascular Regeneration Program at Stanford.

Dr. Yang is a PI of NIH funded Cardiovascular Cell Therapy Research Network designed to conduct multi-center clinical trial on novel stem cell therapy. In addition, he leads 3 NIH and 1 CIRM research grants and 4 clinical trials. He has received several prestigious awards, including NIH Career Development Award, NIH Career Enhancement Award in Stem Cell Biology, NIH Midcareer Award, and multiple awards from both AHA and ACC. He is a frequent guest speaker and session chair at national and international meetings.

Clinical Trials

Efficacy of EVP 1001-1 (SeeMore) in the Assessment of Myocardial Viability in Patients With Cardiovascular DiseaseNot Recruiting

We hope to introduce a novel MRI contrast agent with SeeM ore ? that directly defines viable
myocardium. Identifying viable myocardium non-invasively using cardiac MRI is still a moving
target and a question we plan to answer more definitively with the SeeMore ? contrast.
Though well tested. in small and large animals and Phase I & II clinical trials, we would
like to determine the efficacy of the SeeM ore TM contrast further in a clinical setting.
SeeM ore ? is a new manganese (Mn)-based intravenous imaging agent being developed to
enhance magnetic resonance imaging (MRI). While Mn has long been known to have desirable
magnetic and kinetic properties for MRI, use in humans was not initially possible due to
cardiovascular depression and electrocardiogram (ECG)changes, including prolongation of PR
and QTc intervals, associated with intravenous administration [1-5]. Chelation of Mn, as had
been done with gadolinium for use with MRI, provided relevant safety, but sacrificed
desirable magnetic and kinetic properties [6]. SeeM ore rM provides Mn in a form that
maintains the desired magnetic and kinetic properties while overcoming the cardiovascular
toxicity of Mn. SeeM ore rM is taken up into heart cells .(primarily via addition of calcium
to avoid cardiotoxic effects; please refer to US patent #5,980,863). The potential to
distinguish healthy heart tissue from unhealthy heart tissue based on a specific sustained
pattern of enhancement provides a basis for evaluating the performance of SeeM ore rM in
heart patients. MRI offers benefits over other imaging technologies. Relative to radioactive
nuclear imaging procedures, MRI is 3-dimensional, provides good soft tissue discrimination,
and is of high spatial and temporal resolution. These features have been reported to
identify smaller defects (e.g., subendocardial infarcts) and match angiographic results more
closely than other modalities such as SPECT [7,8]. It may be possible to enhance the utility
of MRI for heart disease further through the use of an imaging agent that is specifically
taken up into heart cells. SeeM ore rM is the only cardiac-specific agent being developed
for this purpose. Unlike nuclear perfusion agents, SeeM ore rM is not radioactive and does
not require special handling, shielding, transport or storage. In addition, the specific
pattern of enhancement achieved in the heart muscle persists over time, offering potential
.benefits over the nonspecific extracellular agents currently available for MRI or X-ray/CT
procedures. This feature allows full use of the high resolution of MRI, since there is not a
trade-off of high spatial resolution for temporal (first-pass) resolution. It is anticipated
the features offered by SeeMore? along with the high resolution, three dimensional
attributes of MRI will result in higher accuracy than is available with other current
modalities in practice, including stress echocardiograms, cardiac MRI using gadolinium
contrast and nuclear studies such as SPECT and PET. This will be evaluated in this study and
serve as the basis for pivotal registration studies.
All components of SeeMore? are USP and are approved for use as drugs in man, orally and/or
intravenously. A summary of the Phase I safety and PK (pharmacokinetics)study are provided
below.
The Phase I study evaluated the safety and tolerance of SeeM ore ? in humans, with special
emphasis on cardiovascular safety, and assessed its PK profile.

The purpose of this study is to find out if aldehyde dehydrogenase bright (ALDHbr) cells
taken from a patient's bone marrow can be placed safely, via intramuscular injections, into
their affected calf and lower thigh muscles and improve blood flow and/or peak walking time
in patients experiencing pain associated with blocked blood vessels in the leg.

The primary purpose of this study is to examine the safety and feasibility of delivering
allogeneic human mesenchymal stem cells (allo-MSCs) by transendocardial injection to cancer
survivors with left ventricular (LV) dysfunction secondary to anthracycline-induced
cardiomyopathy (AIC).
The secondary purpose of this study is to obtain preliminary evidence for therapeutic
efficacy of allo-MSCs delivered by transendocardial injection to cancer survivors with LV
dysfunction secondary to AIC.

Stanford is currently not accepting patients for this trial.For more information, please contact Fouzia Khan, 650-736-1410.

Efficacy and Safety of Allogeneic Mesenchymal Precursor Cells (Rexlemestrocel-L) for the Treatment of Heart Failure.Recruiting

The primary objective of this study is to determine whether transendocardial delivery of
allogeneic human bone marrow-derived MPCs (rexlemestrocel-L) is effective in the treatment
of chronic heart failure due to LV systolic dysfunction.

This is a phase II, randomized, placebo-controlled clinical trial designed to assess
feasibility, safety, and effect of autologous bone marrow-derived mesenchymal stem cells
(MSCs) and c-kit+ cardiac stem cells (CSCs) both alone and in combination (Combo), compared
to placebo (cell-free Plasmalyte-A medium) as well as each other, administered by
transendocardial injection in subjects with ischemic cardiomyopathy.

An Evaluation of a Developmentally-Based Parent Training Program for Children With AutismNot Recruiting

The purpose of this study is to assess the efficacy of a parent training program in the
treatment of social and communication deficits in children with autism. Specifically, this
study will evaluate a developmentally based parent delivered intervention in the community
developed by Pacific Autism Center for Education (PACE).

Stanford is currently not accepting patients for this trial.For more information, please contact Christina Ardel, MA, 650-736-1235.

Abstract

: An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions.Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials.

Abstract

Stem cell therapy has broad applications in regenerative medicine and increasingly within cardiovascular disease. Stem cells have emerged as a leading therapeutic option for many diseases and have broad applications in regenerative medicine. Injuries to the heart are often permanent due to the limited proliferation and self-healing capability of cardiomyocytes; as such, stem cell therapy has become increasingly important in the treatment of cardiovascular diseases. Despite extensive efforts to optimize cardiac stem cell therapy, challenges remain in the delivery and monitoring of cells injected into the myocardium. Other fields have successively used nanoscience and nanotechnology for a multitude of biomedical applications, including drug delivery, targeted imaging, hyperthermia, and tissue repair. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been widely employed for molecular and cellular imaging. In this mini-review, we focus on the application of superparamagnetic iron oxide nanoparticles in targeting and monitoring of stem cells for the treatment of myocardial infarctions.

Abstract

Therapeutic delivery of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) represents a novel clinical approach to regenerate the injured myocardium. However, methods for robust and accurate in vivo monitoring of the iCMs are still lacking. Although superparamagnetic iron oxide nanoparticles (SPIOs) are recognized as a promising tool for in vivo tracking of stem cells using magnetic resonance imaging (MRI), their signal persists in the heart even weeks after the disappearance of the injected cells. This limitation highlights the inability of SPIOs to distinguish stem cell viability. In order to overcome this shortcoming, we demonstrate the use of a living contrast agent, magneto-endosymbionts (MEs) derived from magnetotactic bacteria for the labeling of iCMs. The ME-labeled iCMs were injected into the infarcted area of murine heart and probed by MRI and bioluminescence imaging (BLI). Our findings demonstrate that the MEs are robust and effective biological contrast agents to track iCMs in an in vivo murine model. We show that the MEs clear within one week of cell death whereas the SPIOs remain over 2 weeks after cell death. These findings will accelerate the clinical translation of in vivo MRI monitoring of transplanted stem cell at high spatial resolution and sensitivity.

Abstract

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.

Abstract

Although stem cell therapy (SCT) is emerging as a potential treatment for patients with dilated cardiomyopathy (DCM), clinical response remains variable. Our objective was to determine whether baseline differences in circulating immunologic and nonimmunologic biomarkers may help to identify patients more likely to respond to intramyocardial injection of CD34(+)-based SCT.We enrolled from January 3, 2011 to March 5, 2012 37 patients with longstanding DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral CD34(+) stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) and collection by means of apheresis. CD34(+) cells were labeled with (99m)Tc-hexamethylpropyleneamine oxime to allow assessment of stem cell retention at 18 hours. Response to SCT was predefined as an increase in LVEF of ?5% at 3 months. The majority (84%) of patients were male with an overall mean LVEF of 27 ± 7% and a median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 2,774 pg/mL. Nineteen patients (51%) were responders to SCT. There was no significant difference between responders and nonresponders regarding to age, sex, baseline LVEF, NT-proBNP levels, or 6-minute walking distance. With the use of a partial least squares (PLS) predictive model, we identified 9 baseline factors that were associated with both stem cell response and stem cell retention (mechanistic validation). Among the baseline factors positively associated with both clinical response and stem cell retention were G-CSF, SDF-1, LIF, MCP-1, and MCP-3. Among baseline factors negatively associated with both clinical response and retention were IL-12p70, FASL, ICAM-1, and GGT. A decrease in G-CSF at 3-month follow-up was also observed in responders compared with nonresponders (P = .02).If further validated, baseline immunologic and nonimmunologic biomarkers may help to identify patients with DCM who are more likely to respond to CD34(+)-based SCT.

Abstract

Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.

Abstract

Therapeutic delivery of cardiomyocytes derived from human pluripotent stem cells (hPSC-CMs) represents a novel clinical approach to regenerate the injured myocardium. However, poor survival and contractility of these cells are a significant bottleneck to their clinical use. To better understand the role of cell-cell communication in enhancing the phenotype and contractile properties of hPSC-CMs, we developed a three-dimensional (3D) hydrogel composed of hPSC-CMs, human pluripotent stem cell-derived endothelial cells (hPSC-ECs), and/or human amniotic mesenchymal stem cells (hAMSCs). The objective of this study was to examine the role of multi-cellular interactions among hPSC-ECs and hAMSCs on the survival and long-term contractile phenotype of hPSC-CMs in a 3D hydrogel. Quantification of spontaneous contractility of hPSC-CMs in tri-culture demonstrated a 6-fold increase in the area of contractile motion after 6 weeks with characteristic rhythmic contraction frequency, when compared to hPSC-CMs alone (P < 0.05). This finding was supported by a statistically significant increase in cardiac troponin T protein expression in the tri-culture hydrogel construct at 6 weeks, when compared to hPSC-CMs alone (P < 0.001). The sustained hPSC-CM survival and contractility in tri-culture was associated with a significant upregulation in the gene expression of L-type Ca(2+) ion channel, Cav1.2, and the inward-rectifier potassium channel, Kir2.1 (P < 0.05), suggesting a role of ion channels in mediating these processes. These findings demonstrate that multi-cellular interactions modulate hPSC-CM phenotype, function, and survival, and they will have important implications in engineering cardiac tissues for treatment of cardiovascular diseases.

Abstract

Higher left ventricular volume is associated with death in patients with ESRD. This work investigated the effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling.The Frequent Hemodialysis Network daily trial randomized 245 patients to 12 months of six times per week versus three times per week in-center hemodialysis; the Frequent Hemodialysis Network nocturnal trial randomized 87 patients to 12 months of six times per week nocturnal hemodialysis versus three times per week predominantly home-based hemodialysis. Left and right ventricular end systolic and diastolic volumes, left ventricular mass, and ejection fraction at baseline and end of the study were ascertained by cardiac magnetic resonance imaging. The ratio of left ventricular mass/left ventricular end diastolic volume was used as a surrogate marker of left ventricular remodeling. In each trial, the effect of frequent dialysis on left or right ventricular end diastolic volume was tested between predefined subgroups.In the daily trial, frequent hemodialysis resulted in significant reductions in left ventricular end diastolic volume (-11.0% [95% confidence interval, -16.1% to -5.5%]), left ventricular end systolic volume (-14.8% [-22.7% to -6.2%]), right ventricular end diastolic volume (-11.6% [-19.0% to -3.6%]), and a trend for right ventricular end systolic volume (-11.3% [-21.4% to 0.1%]) compared with conventional therapy. The magnitude of reduction in left and right ventricular end diastolic volumes with frequent hemodialysis was accentuated among patients with residual urine output<100 ml/d (P value [interaction]=0.02). In the nocturnal trial, there were no significant changes in left or right ventricular volumes. The frequent dialysis interventions had no substantial effect on the ratio of left ventricular mass/left ventricular end diastolic volume in either trial.Frequent in-center hemodialysis reduces left and right ventricular end systolic and diastolic ventricular volumes as well as left ventricular mass, but it does not affect left ventricular remodeling.

Abstract

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

Abstract

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

Abstract

Human amniotic mesenchymal stem cells (hAMSCs) demonstrated partially pluripotent characteristics with a strong expression of Oct4 and Nanog genes and immunomodulatory properties characterized by the absence of HLA-DR and the presence of HLA-G and CD59. The hAMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) that generate a promising source of universal cardiac cells. The hAMSC-derived iPSCs (MiPSCs) successfully underwent robust cardiac differentiation to generate cardiomyocytes. This study investigated 3 key properties of the hAMSCs and MiPSCs: (1) the reprogramming efficiency of the partially pluripotent hAMSCs to generate MiPSCs; (2) immunomodulatory properties of the hAMSCs and MiPSCs; and (3) the cardiac differentiation potential of the MiPSCs. The characteristic iPSC colony formation was observed within 10 days after the transduction of the hAMSCs with a single integration polycistronic vector containing 4 Yamanaka factors. Immunohistology and reverse transcription-polymerase chain reaction assays revealed that the MiPSCs expressed stem cell surface markers and pluripotency-specific genes. Furthermore, the hAMSCs and MiPSCs demonstrated immunomodulatory properties enabling successful engraftment in the SVJ mice. Finally, the cardiac differentiation of MiPSCs exhibited robust spontaneous contractility, characteristic calcium transience across the membrane, a high expression of cardiac genes and mature cardiac phenotypes, and a contractile force comparable to cardiomyocytes. Our results demonstrated that the hAMSCs are reprogrammed with a high efficiency into MiPSCs, which possess pluripotent, immunomodulatory, and precardiac properties. The MiPSC-derived cardiac cells express a c-kit cell surface marker, which may be employed to purify the cardiac cell population and enable allogeneic cardiac stem cell therapy.

Abstract

Spurred by remarkable findings in animal studies, there has been strong interest in evaluating the potential of adult stem cells to improve left ventricular function in the past decade. Driven by the need to treat the increasing number of patients with coronary artery disease, numerous studies have attempted to define a role for bone marrow cell therapy in clinical use. However, the conflicting results of these studies can be confusing. This article will review the landmark trials evaluating bone marrow cell therapy in the past decade and describe the current state of adult stem cell therapy and its future direction herein.

Abstract

Apelin is a peptide ligand for an orphan G-protein coupled receptor (APJ receptor) and serves as a critical gradient for migration of mesodermal cells fated to contribute to the myocardial lineage. The present study was designed to establish a robust cardiac differentiation protocol, specifically, to evaluate the effect of apelin on directed differentiation of mouse and human embryonic stem cells (mESCs and hESCs) into cardiac lineage. Different concentrations of apelin (50, 100, 500 nM) were evaluated to determine its differentiation potential. The optimized dose of apelin was then combined with mesodermal differentiation factors, including BMP-4, activin-A, and bFGF, in a developmentally specific temporal sequence to examine the synergistic effects on cardiac differentiation. Cellular, molecular, and physiologic characteristics of the apelin-induced contractile embryoid bodies (EBs) were analyzed. It was found that 100 nM apelin resulted in highest percentage of contractile EB for mESCs while 500 nM had the highest effects on hESCs. Functionally, the contractile frequency of mESCs-derived EBs (mEBs) responded appropriately to increasing concentration of isoprenaline and diltiazem. Positive phenotype of cardiac specific markers was confirmed in the apelin-treated groups. The protocol, consisting of apelin and mesodermal differentiation factors, induced contractility in significantly higher percentage of hESC-derived EBs (hEBs), up-regulated cardiac-specific genes and cell surface markers, and increased the contractile force. In conclusion, we have demonstrated that the treatment of apelin enhanced cardiac differentiation of mouse and human ESCs and exhibited synergistic effects with mesodermal differentiation factors.

Abstract

An increase in left ventricular mass (LVM) is associated with mortality and cardiovascular morbidity in patients with end-stage renal disease.The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to 12 months of 6 times per week daily in-center hemodialysis or conventional hemodialysis; the FHN Nocturnal Trial randomized 87 patients to 12 months of 6 times per week nocturnal hemodialysis or conventional hemodialysis. The main cardiac secondary outcome was change in LVM. In each trial, we examined whether several predefined baseline demographic or clinical factors as well as change in volume removal, blood pressure, or solute clearance influenced the effect of frequent hemodialysis on LVM. In the Daily Trial, frequent hemodialysis resulted in a significant reduction in LVM (13.1 g; 95% CI, 5.0-21.3 g; P=0.002), LVM index (6.9 g/m(2); 95% CI, 2.4-11.3 g/m(2); P=0.003), and percent change in geometric mean of LVM (7.0%; 95% CI, 1.0%-12.6; P=0.02). Similar trends were noted in the Nocturnal Trial but did not reach statistical significance. In the Daily Trial, a more pronounced effect of frequent hemodialysis on LVM was evident among patients with left ventricular hypertrophy at baseline. Changes in LVM were associated with changes in blood pressure (conventional hemodialysis: R=0.28, P=0.01, daily hemodialysis: R=0.54, P<0.001) and were not significantly associated with changes in other parameters.Frequent in-center hemodialysis reduces LVM. The benefit of frequent hemodialysis on LVM may be mediated by salutary effects on blood pressure. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00264758.

Abstract

Cellular apoptosis is a prominent feature of many diseases, and this programmed cell death typically occurs before clinical manifestations of disease are evident. A means to detect apoptosis in its earliest, reversible stages would afford a pre-clinical 'window' during which preventive or therapeutic measures could be taken to protect the heart from permanent damage. We present herein a simple and robust method to conjugate human Annexin V (ANX), which avidly binds to cells in the earliest, reversible stages of apoptosis, to superparamagnetic iron oxide (SPIO) nanoparticles, which serve as an MRI-detectable contrast agent. The conjugation method begins with an oxidation of the SPIO nanoparticles, which oxidizes carboxyl groups on the polysaccharide shell of SPIO. Purified ANX protein is then added in the setting of a sodium borate solution to facilitate covalent interaction of ANX with SPIO in a reducing buffer. A final reduction step with sodium borohydride is performed to complete the reduction, and then the reaction is quenched. Unconjugated ANX is removed from the mix by microcentrifuge filtration. The size and purity of the ANX-SPIO product is verified by dynamic light scattering (DLS). This method does not require addition to, or modification of, the polysaccharide SPIO shell, as opposed to cross-linked iron oxide particle conjugation methods or biotin-labeled nanoparticles. As a result, this method represents a simple, robust approach that may be extended to conjugation of other proteins of interest.

Abstract

Embryonic stem cells (ESCs) have shown the potential to restore cardiac function after myocardial injury. Superparamagnetic iron oxide nanoparticles (SPIO) have been widely employed to label ESCs for cellular MRI. However, nonspecific intracellular accumulation of SPIO limits long-term in vivo assessment of the transplanted cells. To overcome this limitation, a novel reporter gene (RG) has been developed to express antigens on the ESC surface. By employing SPIO-conjugated monoclonal antibody against these antigens (SPIO-MAb), the viability of transplanted ESCs can be detected in vivo. This study aims to develop a new molecular MRI method to assess in vivo ESC viability, proliferation, and teratoma formation. The RG is designed to express 2 antigens (hemagglutinin A and myc) and luciferase on the ESC surface. The two antigens serve as the molecular targets for SPIO-MAb. The human and mouse ESCs were transduced with the RG (ESC-RGs) and transplanted into the peri-infarct area using the murine myocardial injury model. In vivo MRI was performed following serial intravenous administration of SPIO-MAb. Significant hypointense signal was generated from the viable and proliferating ESCs and subsequent teratoma. This novel molecular MRI technique enabled in vivo detection of early ESC-derived teratoma formation in the injured murine myocardium.

Abstract

Cell death by apoptosis is critical in myocardial diseases, and noninvasive detection of early, reversible apoptosis might be useful clinically. Exogenous Annexin-V (ANX) protein binds membrane phosphatidylserine, which is externalized in early apoptosis. A molecular MRI probe was constructed with superparamagnetic iron oxide (SPIO) conjugated to recombinant human ANX (ANX-SPIO). Apoptosis was induced with doxorubicin, a cardiotoxic cancer drug, in culture in neonatal rat ventricular myocytes, cardiac fibroblasts, and mesenchymal stem cells, and in vivo in the mouse heart. ANX-SPIO was validated using T2*-weighted 3T MRI. ANX-SPIO produced T2* signal loss, reflecting iron content, that correlated highly with independent apoptosis markers; bound with high affinity to apoptotic myocytes by competition assay (Ki 69 nM); detected apoptosis in culture much earlier than did TUNEL stain; and revealed fibroblast resistance to apoptosis. With apoptosis in vivo, ANX-SPIO produced diffuse myocardial T2* signal loss that correlated with increased iron stain and caspase activity. Treatment with an alpha-1-adrenergic agonist in vivo reversed apoptosis and eliminated the ANX-SPIO MRI signal. It is concluded that cardiac MRI of ANX-SPIO detects early, nonischemic cardiac apoptosis in culture and in vivo, and can identify reversibly injured cardiac cells in diseased hearts, when treatment is still possible.

Abstract

To date, the underlying mechanism responsible for the restoration of the injured myocardium following transplantation of stem cells has not been clearly identified. Molecular imaging is essential to the continued progress of stem cell therapy by elucidating the biology of transplanted stem cells in vivo. Currently, several imaging modalities are in development in the rapidly evolving field of molecular imaging. Contrast echocardiography has the potential to define its role in shaping the future development of stem cell therapy. We describe the current state of contrast echocardiography and its future direction herein.

Abstract

Obstructive sleep apnea (OSA) has been associated with cardiovascular disease (CVD), but whether OSA is an independent risk factor for CVD is controversial. The purpose of this study is to determine if patients with OSA have subclinical cardiovascular disease that is detectable by multi-modality cardiovascular imaging and whether these abnormalities improve after nasal continuous positive airway pressure (nCPAP).Of the 35 consecutive subjects with newly diagnosed moderate to severe OSA recruited from the Stanford Sleep Disorders Clinic, 20 patients were randomized to active vs. sham nCPAP. Active nCPAP was titrated to pressures that would prevent sleep disordered breathing based on inpatient polysomnography. OSA patients had baseline vascular function abnormalities including decreased myocardial perfusion reserve (MPR), brachial flow mediated dilation (FMD) and nitroglycerin-induced coronary vasodilation. Patients randomized to active nCPAP had improvement of MPR (1.5 ± 0.5 vs. 3.0 ± 1.3, p = 0.02) and brachial FMD (2.5% ± 5.7% vs. 9.0% ± 6.5%, p = 0.03) after treatment, but those randomized to sham nCPAP showed no significant improvement. There were no significant changes seen in chamber sizes, systolic and diastolic function, valvular function and coronary vasodilation to nitroglycerin.Patients with moderate to severe OSA had decreased MPR and brachial FMD that improved after 3 months of nCPAP. These findings suggest that relief of apnea in OSA may improve microvascular disease and endothelial dysfunction, which may prevent the development of overt cardiovascular disease. Further study in a larger patient population may be warranted.

Abstract

This study evaluates how characterization of tissue heterogeneity of myocardial infarction by cardiovascular magnetic resonance (CMR) is associated with cardiovascular events (CVE) in patients with ischemic cardiomyopathy (ICM).Prior studies demonstrated that the quantification of myocardial scar volume by CMR is superior to left ventricular end-diastolic volume, left ventricular end-systolic volume, and left ventricular ejection fraction (LVEF) in predicting future CVE in ICM patients. Evaluation of infarct heterogeneity by measuring infarct core and border zones through CMR might have a higher association with CVE.Seventy patients (mean LVEF: 25 +/- 11%) considered for revascularization or medical management +/- implantable cardiac defibrillator were enrolled. A 1.5-T GE MRI (Signa, GE Healthcare, Milwaukee, Wisconsin) was used to acquire cine and delayed enhancement images. The patients' core and border zones of infarcted myocardium were analyzed and followed for CVE.Larger infarct border zone and its percentage of myocardium were found in the 29 patients (41%) who had CVE (median 13.3 g [interquartile range (IQR) 8.4 to 25.1 g] vs. 8.0 g [IQR 3.0 to 14.5 g], p = 0.02 and 7.8% [IQR 4.9% to 17.0%] vs. 4.1% [IQR 1.9% to 9.3%], p = 0.02, respectively). The core infarct zone and its percentage of myocardium, left ventricular end-diastolic volume, left ventricular end-systolic volume, and LVEF were not statistically significant. Sub-analysis of the medical management and revascularization patients with CVE demonstrated that the medically managed patients had a larger border zone, whereas there was no difference between border and core zones in the revascularization group (p < 0.05).Quantification of core and border zones and their percentages of myocardium through CMR is associated with future CVE and might assist in the management of patients with ICM.

Abstract

There has been recent interest in positive-contrast MRI methods for noninvasive tracking of cells labeled with superparamagnetic iron-oxide nanoparticles. Low-tip-angle balanced steady-state free precession sequences have been used for fast, high-resolution, and flow-insensitive positive-contrast imaging; however, the contrast can be compromised by the limited suppression of the on-resonant and fat signals. In this work, a new technique that produces positive contrast with alternating repetition time steady-state free precession is proposed to achieve robust background suppression for a broad range of tissue parameters. In vitro and in vivo experiments demonstrate the reliability of the generated positive contrast. The results indicate that the proposed method can enhance the suppression level by up to 18 dB compared with conventional balanced steady-state free precession.

Abstract

Stem cell therapy has been heralded as a novel therapeutic option for cardiovascular disease. In vivo molecular imaging has emerged as an indispensible tool in investigating stem cell biology post-transplantation into the myocardium and in evaluating the therapeutic efficacy. This review highlights the features of each molecular imaging modality and discusses how these modalities have been applied to evaluate stem cell therapy.

Abstract

This study investigated the ability of MnCl(2) as a cellular MRI contrast agent to determine the in vitro viability of human embryonic stem cells (hESC) and human bone marrow stromal cells (hBMSC). Basic MRI parameters including T(1) and T(2) values of MnCl(2)-labeled hESC and hBMSC were measured and viability signal of manganese (Mn(2+))-labeled cells was validated. Furthermore, the biological activity of Ca(2+)-channels was modulated utilizing both Ca(2+)-channel agonist and antagonist to evaluate concomitant signal changes. Metabolic effects of MnCl(2)-labeling were also assessed using assays for cell viability, proliferation, and apoptosis. Finally, in vivo Mn(2+)-guided MRI of the transplanted hESC was successfully achieved and validated by bioluminescence imaging.

Abstract

Magnetic resonance imaging (MRI) may emerge as an ideal non-invasive imaging modality to monitor stem cell therapy in the failing heart. This imaging modality generates any arbitrary tomographic view at high spatial and temporal resolution with exquisite intrinsic tissue contrast. This capability enables robust evaluation of both the cardiac anatomy and function. Traditionally, superparamagnetic iron oxide nanoparticle (SPIO) has been widely used for cellular MRI due to SPIO's ability to enhance sensitivity of MRI by inducing remarkable hypointense, negative signal, "blooming effect" on T2*-weighted MRI acquisition. Recently, manganese chloride (MnCl(2)) has been reported by our laboratory for its ability as a contrast agent to track biological activity of viable cells. Hyperintense, positive signals can be achieved from the Mn(2+)-labeled stem cells on T1-weighted MRI acquisition. Cytotoxicity is a potential drawback of Mn(2+) labeling of the cells. However, in our laboratory the labeling method has been optimized to minimize cytotoxic effects. This article describes two different magnetic labeling methods of human embryonic stem cells (hESC) using SPIO and MnCl(2).

Abstract

MRI has been used extensively to noninvasively track the location of cells labeled with superparamagnetic iron-oxide nanoparticles (SPIOs) in vivo. Typically, SPIOs are employed as a negative contrast agent which makes it difficult to differentiate labeled cells from extraneous sources of inhomogeneity and actual voids in the image. As a result, several novel approaches have been put forth to obtain positive contrast from SPIOs. One technique proposed by Cunningham et al. utilizes spectrally selective pulses to excite and refocus spins in the vicinity of the SPIOs. Although the frequency selectivity of this technique provides effective positive contrast, the lack of slice selectivity results in interfering signal from sources of off-resonance outside the slice of interest. We have developed a self-refocused spatial-spectral (SR-SPSP) pulse to achieve slice-selective spin-echo imaging of off-resonant spins. Using a self-refocused pulse affords flexibility in echo-time selection since the spin echo may be placed at any time after the end of the pulse. The spatial selectivity achieved by the SR-SPSP RF pulse eliminates background signal from out-of-slice regions and reduces the on-resonant water suppression requirements. Phantom and in vivo data demonstrate that positive contrast and slice-selectivity are achieved using this novel RF pulse.

Abstract

MRI is emerging as a diagnostic modality to track iron-oxide-labeled stem cells. This study investigates whether an off-resonance (OR) pulse sequence designed to generate positive contrast at 1.5T can assess the location, quantity, and viability of delivered stem cells in vivo. Using mouse embryonic stem cell transfected with luciferase reporter gene (luc-mESC), multimodality validation of OR signal was conducted to determine whether engraftment parameters of superparamagnetic iron-oxide labeled luc-mESC (SPIO-luc-mESC) could be determined after cell transplantation into the mouse hindlimb. A significant increase in signal- and contrast-to-noise of the SPIO-luc-mESC was achieved with the OR technique when compared to a gradient recalled echo (GRE) sequence. A significant correlation between the quantity of SPIO-luc-mESC and OR signal was observed immediately after transplantation (R(2) = 0.74, P < 0.05). The assessment of transplanted cell viability by bioluminescence imaging (BLI) showed a significant increase of luciferase activities by day 16, while the MRI signal showed no difference. No significant correlation between BLI and MRI signals of cell viability was observed. In conclusion, using an OR sequence the precise localization and quantitation of SPIO-labeled stem cells in both space and time were possible. However, the OR sequence did not allow evaluation of cell viability.

Abstract

We tested the hypothesis that multimodality imaging of mouse embryonic stem cells (mESCs) provides accurate assessment of cellular location, viability, and restorative potential after transplantation into different zones of myocardial infarction.Mice underwent left anterior descending artery ligation followed by transplantation of dual-labeled mESCs with superparamagnetic iron oxide and luciferase via direct injection into 3 different zones of myocardial infarction: intra-infarction, peri-infarction, and normal (remote). One day after transplantation, magnetic resonance imaging enabled assessment of the precise anatomic locations of mESCs. Bioluminescence imaging allowed longitudinal analysis of cell viability through detection of luciferase activity. Subsequent evaluation of myocardial regeneration and functional restoration was performed by echocardiography and pressure-volume loop analysis. Using 16-segment analysis, we demonstrated precise localization of dual-labeled mESCs. A strong correlation between histology and magnetic resonance imaging was established (r=0.962, P=0.002). Bioluminescent imaging data demonstrated that cell viability in the remote group was significantly higher than in other groups. Echocardiography and pressure-volume loop analysis revealed improved functional restoration in animals treated with mESCs, although myocardial regeneration was not observed.Multimodality evaluation of mESC engraftment in the heterogeneous tissue of myocardial infarction is possible. Magnetic resonance imaging demonstrated accurate anatomic localization of dual-labeled mESCs. Bioluminescent imaging enabled assessment of variable viability of mESCs transplanted into the infarcted myocardium. Echocardiography and pressure-volume loop analysis validated the restorative potential of mESCs. Although mESCs transplanted into the remote zone demonstrated the highest viability, precise delivery of mESCs into the peri-infarction region might be equally critical in restoring the injured myocardium.

Abstract

Human embryonic stem (hES) cells are pluripotent stem cells capable of self-renewal and differentiation into virtually all cell types. Thus, they hold tremendous potential as cell sources for regenerative therapies. The concurrent development of accurate, sensitive, and noninvasive technologies capable of monitoring hES cells engraftment in vivo can greatly expedite basic research prior to future clinical translation. In this study, hES cells were stably transduced with a lentiviral vector carrying a novel double-fusion reporter gene that consists of firefly luciferase and enhanced green fluorescence protein. Reporter gene expression had no adverse effects on cell viability, proliferation, or differentiation to endothelial cells (human embryonic stem cell-derived endothelial cells [hESC-ECs]). To compare the two popular imaging modalities, hES cells and hESC-ECs were then colabeled with superparamagnetic iron oxide particles before transplantation into murine hind limbs. Longitudinal magnetic resonance (MR) imaging showed persistent MR signals in both cell populations that lasted up to 4 weeks. By contrast, bioluminescence imaging indicated divergent signal patterns for hES cells and hESC-ECs. In particular, hESC-ECs showed significant bioluminescence signals at day 2, which decreased progressively over the following 4 weeks, whereas bioluminescence signals from undifferentiated hES cells increased dramatically during the same period. Post-mortem histology and immunohistochemistry confirmed teratoma formation after injection of undifferentiated hES cells but not hESC-ECs. From these data taken together, we concluded that reporter gene is a better marker for monitoring cell viability, whereas iron particle labeling is a better marker for high-resolution detection of cell location by MR. Furthermore, transplantation of predifferentiated rather than undifferentiated hES cells would be more suited for avoiding teratoma formation.

Abstract

In vivo MRI of stem cells (SCs) is an emerging application to evaluate the role of cell therapy in restoring the injured myocardium. The high spatial and temporal resolution combined with iron-oxide-based intracellular labeling techniques will provide a sensitive, noninvasive, dual imaging modality for both cells and myocardium. In order to facilitate this novel imaging approach, much effort has been directed towards developing efficient transfection methods. While techniques utilizing poly-L-lysine (PLL), protamine sulfate (PS), and electroporation (ELP) have been proposed, the fundamental biological effects of these methods on mouse embryonic SCs (mESC) have not been investigated systematically. In this study a longitudinal in vitro evaluation of cellular viability, apoptosis, proliferation, and cardiac differentiation of magnetically labeled mESC was conducted. No significant difference was seen in these biological parameters among the three transfection methods. However, cardiac differentiation was most attenuated by ELP, and iron uptake was most effective by PS.

Abstract

Stem cell therapy may provide an alternative therapeutic option for severe congestive heart failure (CHF). Despite the promise generated by this novel approach, precise in vivo monitoring of the transplanted cells and of subsequent myocardial restoration remains a challenge. The development of a sensitive, noninvasive imaging technology to track stem cells while assessing cardiac function is critical to monitor therapeutic efficacy. In vivo cardiovascular MRI of stem cells is an emerging application to identify, localize, and monitor stem cells while simultaneously evaluating the restoration of the injured myocardium following stem cell therapy. Furthermore, advances in scanner technology, pulse sequence design, and associated hardware have resulted in real-time guidance of catheter-based intervention to deliver cells accurately to the regions of myocardial injury. These capabilities have positioned MRI as the primary comprehensive imaging modality to monitor cell therapy.

Abstract

Nanocrystals with advanced magnetic or optical properties have been actively pursued for potential biological applications, including integrated imaging, diagnosis and therapy. Among various magnetic nanocrystals, FeCo has superior magnetic properties, but it has yet to be explored owing to the problems of easy oxidation and potential toxicity. Previously, FeCo nanocrystals with multilayered graphitic carbon, pyrolytic carbon or inert metals have been obtained, but not in the single-shelled, discrete, chemically functionalized and water-soluble forms desired for biological applications. Here, we present a scalable chemical vapour deposition method to synthesize FeCo/single-graphitic-shell nanocrystals that are soluble and stable in water solutions. We explore the multiple functionalities of these core-shell materials by characterizing the magnetic properties of the FeCo core and near-infrared optical absorbance of the single-layered graphitic shell. The nanocrystals exhibit ultra-high saturation magnetization, r1 and r2 relaxivities and high optical absorbance in the near-infrared region. Mesenchymal stem cells are able to internalize these nanoparticles, showing high negative-contrast enhancement in magnetic-resonance imaging (MRI). Preliminary in vivo experiments achieve long-lasting positive-contrast enhancement for vascular MRI in rabbits. These results point to the potential of using these nanocrystals for integrated diagnosis and therapeutic (photothermal-ablation) applications.

Abstract

Cell therapy has demonstrated the potential to restore injured myocardium. A reliable in vivo imaging method to localize transplanted cells and monitor their restorative effects will enable a systematic investigation of this therapeutic modality. The dual MRI capability of imaging both magnetically labeled mouse embryonic stem cells (mESC) and their restorative effects on cardiac function in a murine model of acute myocardial infarction is demonstrated. Serial in vivo MR detection of transplanted mESC and monitoring of the mESC-treated myocardium was conducted over a 4-week period using a 1.5 T clinical scanner. During the 4-week duration, the mESC-treated myocardium demonstrated sustained improvement of the left ventricular (LV) ejection fraction and conservation of LV mass. Furthermore, no significant difference of their restorative effects on the cardiac function was created by the magnetic labeling of mESC. Thus, in vivo MRI enables simultaneous detection of transplanted mESC and their therapeutic effect on the injured myocardium.

Abstract

Recently, indirect magnetic resonance lymphangiography with gadolinium (Gd) has been demonstrated to offer the potential for safe, high-resolution visualization of the lymphatic vessels, in addition to the lymph nodes. In this study, the potential utility of indirect Gd contrast magnetic resonance imaging of lymphatic vascular function was investigated in the murine tail. Functional imaging of healthy mice is contrasted with the findings in experimentally-induced lymphatic vascular insufficiency.Postsurgical lymphedema was experimentally created in the murine tail. Normal and lymphedematous mouse tails were imaged following direct subcutaneous administration of Gadolinium-DTPA, 0.1 mmol/kg. Images were obtained in axial and coronal planes with a T1-weighted spin echo inversion-recovery sequence.In the normal tail, both of the bilateral major collecting lymphatics were clearly visualized as the Gd tracer was cleared from the interstitial compartment. In contrast, the Gd tracer accumulated at the prior surgical site in the lymphedematous tail. Quantitative assessment of Gd clearance demonstrates that accumulation of Gd correlates with the impedance to lymph flow proximal to the site of surgical lymphatic ablation.Magnetic resonance is a feasible and reliable method to be applied to quantitative functional imaging of the lymphatic vasculature in experimental models of lymphedema.

Abstract

To study the feasibility of a combined high spatial and temporal resolution real-time spiral MRI sequence for guiding coronary-sized vascular interventions.Eight New Zealand White rabbits (four normal and four with a surgically-created stenosis in the abdominal aorta) were studied. A real-time interactive spiral MRI sequence combining 1.1 x 1.1 mm(2) in-plane resolution and 189-msec total image acquisition time was used to image all phases of an interventional procedure (i.e., guidewire placement, balloon angioplasty, and stenting) in the rabbit aorta using coronary-sized devices on a 1.5 T MRI system.Real-time spiral MRI identified all rabbit aortic stenoses and provided high-temporal-resolution visualization of guide-wires crossing the stenoses in all animals. Angioplasty balloon dilatation and deployment of coronary-sized copper stents in the rabbit aorta were also successfully imaged by real-time spiral MRI.Combining high spatial and temporal resolution with spiral MRI allows real-time MR-guided vascular intervention using coronary-sized devices in a rabbit model. This is a promising approach for guiding coronary interventions.

Abstract

Contrast agents incorporating superparamagnetic iron-oxide nanoparticles have shown promise as a means to visualize labeled cells using MRI. Labeled cells cause significant signal dephasing due to the magnetic field inhomogeneity induced in water molecules near the cell. With the resulting signal void as the means for detection, the particles behave as a negative contrast agent, which can suffer from partial-volume effects. In this paper, a new method is described for imaging labeled cells with positive contrast. Spectrally selective RF pulses are used to excite and refocus the off-resonance water surrounding the labeled cells so that only the fluid and tissue immediately adjacent to the labeled cells are visible in the image. Phantom, in vitro, and in vivo experiments show the feasibility of the new method. A significant linear correlation (r = 0.87, P < 0.005) between the estimated number of cells and the signal was observed.

Abstract

The purpose of this study was to investigate the use of coronary magnetic resonance angiography (MRA) for assessing human epicardial coronary artery vasodilation.Coronary vasodilation plays a vital role in the human coronary circulation. Previous studies of epicardial coronary vasodilation have used invasive coronary angiography. Coronary MRA may provide an alternative noninvasive method to directly assess changes in coronary size.Thirty-two subjects were studied: 12 patients (age 55 +/- 18 years) and 20 healthy subjects (age 34 +/- 4 years). High-resolution multi-slice spiral coronary MRA (in-plane resolution of 0.52 to 0.75 mm) was performed before and after sublingual nitroglycerin (NTG). Quantitative analysis of coronary vasodilation was performed on cross-sectional images of the right coronary artery (RCA). A time-course analysis of coronary vasodilation was performed in a subset of eight subjects for 30 min after NTG. Signal-to-noise ratio was also measured on the in-plane RCA images.Coronary MRA demonstrated a 23% increase in cross-sectional area after NTG (16.9 +/- 7.8 mm2 to 20.8 +/- 8.9 mm2, p <0.0001), with significant vasodilation between 3 and 15 min after NTG on time-course analysis. The MRA measurements had low interobserver variability (< or =5%) and good correlation with X-ray angiography (r=0.98). The magnitude of vasodilation correlated with baseline cross-sectional area (r=0.52, p=0.03) and age (r=0.40, p=0.019). Post-NTG images also demonstrated a 31% improvement in coronary signal-to-noise ratio (p = 0.002).Nitroglycerin-enhanced coronary MRA can noninvasively measure coronary artery vasodilation and is a promising noninvasive technique to study coronary vasomotor function.

Abstract

The hallmark of hemochromatosis is the deposition of iron in multiple tissue types, most notably the skin, liver, pancreas, thyroid, and heart. Definitive diagnosis of iron deposition generally requires invasive methods, such as direct tissue biopsy. We describe a 40 year-old woman with end-stage liver disease secondary to hereditary hemochromatosis and alcohol abuse, who was referred to the cardiology service as part of an evaluation for orthotopic liver transplant. The patient had no cardiac history but a dobutamine stress echocardiogram, performed as a portion of the pre-operative cardiac evaluation, could not be completed due to intermittent, supraventricular tachycardia. Additional cardiac testing, including electrocardiography and resting echocardiography, raised suspicion for cardiomyopathy related to hemochromatosis but was non-diagnostic. Cardiac magnetic resonance (MR) of this patient revealed deposition of iron in the myocardium and established the diagnosis of hemachromatosis-related cardiomyopathy. These findings suggest that cardiac MR may be more sensitive than other non-invasive, diagnostic tools in the initial evaluation of hemochromatosis-related cardiomyopathy and may be used as an alternative to myocardial biopsy. We propose that conventional T1- and T2-weighted spin echo MR sequences can be used routinely as non-invasive modalities to assess the presence of iron deposition in the tissues of patients with hemochromatosis.

Abstract

MR coronary angiography (MRCA) has been demonstrated successfully at 3 Tesla (T). However, the advantages remain unclear. No systematic comparison of MRCA between 1.5 T and 3 T has been performed. Therefore, anatomic coverage, image quality, signal-to-noise ratio (SNR), contrast-to-noise ration (CNR), and susceptibility artifacts were compared in 23 subjects.Identical real-time (RT) and high-resolution (HR) sequences were implemented on the GE 1.5 T (Signa Twinspeed) and 3.0 T (Signa VH/i) whole body systems (GE, Milwaukee, WI). Both scanners were equipped with high-performance gradient systems capable of 40 mT/m peak amplitude and 150 mT/m/ms slew rate. Real-time localization of the coronary arteries was followed by a cardiac-gated, breath-hold HR sequence. Twenty-three subjects were recruited consecutively and underwent both 3 T and 1.5 T MRCA within one week. Coronary coverage based on the number of coronary segments visualized, image quality using a grading scale, SNR, CNR, and presence of susceptibility artifacts were analyzed. A significant improvement in SNR (47%), CNR (30%), and image quality were seen in 3 T. However, a significant increase in susceptibility artifacts was also noted.MRCA at 3 T significantly improves SNR, CNR, and image quality at the expense of susceptibility artifacts. Further optimization of the imaging parameters at 3 T may facilitate clinical implementation of MRCA.

Abstract

A dynamic real-time (dRT) architecture has been developed to address limitations in magnetic resonance coronary angiography (MRCA). A prospective clinical trial of 45 patients suspected of coronary artery disease was conducted to determine clinical utility of this integrated real-time system.Clinical implementation of MRCA is not performed routinely today. However, improved anatomic coverage, image quality, and scan flexibility may enhance its clinical utility. A novel real-time architecture addresses these challenges through instantaneous reconfiguration between real-time (RT) and high-resolution (HR) imaging sequences with dynamic selection of the desired element on a custom-designed receiver coil.A total of 45 subjects were recruited consecutively to evaluate scan time, anatomic coverage, image quality, and detection of coronary lesions. Using a modern PC, the dRT switches from RT to gated HR imaging sequence in one repetition time (39 ms). Magnetic resonance imaging (MRI) scanning was performed using a custom-designed coronary coil consisting of two four-inch phase-array circular elements enabled with real-time selection of the desired coil element.All studies were completed in less than 45 minutes and required a mean of 12 breath holds (16 heartbeats). Of the total number of coronary segments, 91% (357/394) were visualized. Excellent or good image quality was achieved in 86% of the segments. Blinded analysis of the coronary arteries revealed sensitivity of 93% and specificity of 88% in the detection of coronary stenoses.The integrated environment of dRT provides a rapid and flexible scan protocol for MRCA while achieving wide anatomical coverage, high image quality, and reliable detection of coronary stenosis in short scan time.

Abstract

Previously published reports show that there is significant intraobserver, interobserver, and interinstitutional variability in the determination of left ventricular (LV) ejection fraction (EF) by echocardiography. With the increased deployment of echocardiography (eg, handheld devices), there exists a need for developing a simple, intuitive approach for evaluating LVEF that allows a wider range of physicians to accurately and rapidly determine LVEF.We sought to create a system for assessing LVEF that relies on recognition and matching of patterns, rather than on mathematic calculations and geometric assumptions.A library of videoclips of cardiac function was compiled from 54 patients who spanned the spectrum of LVEF. LVEFs were calculated for these patients using standard echocardiographic methods, with further validation of a subsample using cardiac magnetic resonance imaging measurement of LVEF. The library of images was used to create a software tool for assessing LVEF on the basis of a "template-matching" approach. The software tool was then tested on medical students (N=13) to determine whether it enabled relatively untrained individuals to make accurate LVEF estimates.Using a template-matching approach for interpretation of echocardiograms, medical students were able to accurately estimate LVEF after only a limited introduction to echocardiography. Their LVEF estimates showed good correlation and agreement with gold standard (r = 0.88, standard square of the estimate = 6.0, limits of agreement = +12.0%, -15.6%).A new visual approach for assessing cardiac function using template matching can accurately estimate LVEF. With minimal training, medical students can make LVEF estimates that correlate well with gold standard. The application of this new approach includes allowing for the interpretation of LVEF from echocardiograms to be performed by a broader spectrum of physicians.

Abstract

A spiral high-resolution coronary artery imaging sequence (SH) interfaced with real-time localization system (RT) has been developed. A clinical study of 40 patients suspected of coronary artery disease (CAD) was conducted. Segmented k-space acquisition techniques have dominated magnetic resonance coronary angiography (MRCA) over the last decade. Although a recent multicenter trial using this technique demonstrated encouraging results, the technique was hampered by low specificity. Spiral k-space acquisition had demonstrated several advantages for MRCA. Therefore, a first clinical trial implementing spiral high-resolution coronary imaging sequence with real-time localization (SH-RT) was performed.A clinical study of 40 patients suspected of CAD undergoing X-ray angiography was conducted to analyze the clinical reliability of this novel imaging system. The SH-RT had been designed to exploit the unique capability of two imaging sequences. The RT allowed a rapid localization of the coronary arteries. Then SH achieved multislice acquisition during a short breath-hold with submillimeter resolution. The MRCA data were analyzed for scan time, anatomic coverage, image quality, and accuracy in detecting CAD. In 40 subjects, SH achieved 0.7 to 0.9 mm resolution with 14-heartbeat breath-holds. Excellent or good image quality was achieved in 78% (263/337) of the coronary segments. Blinded consensus reading among three observers generated sensitivity of 76% and specificity of 91% in the detection of CAD compared with X-ray angiography. The MRCA imaging sequence implementing a novel spiral k-space acquisition technique enabled rapid and reliable imaging of the CAD in submillimeter resolution with short breath-holds.

Abstract

Magnetic resonance coronary angiography (MRCA) has witnessed tremendous technical advances over the past decade. Although high-quality images of the coronary arteries have been demonstrated, this imaging modality is not performed routinely today. The fundamental properties of the coronary arteries deterring noninvasive imaging are well known. This article provides an overview of the developmental efforts to overcome these challenges, and highlights key technical and clinical advances. The future prospect of MRCA depends on clinical implementation of the technique. In order to meet this challenge, the following issues must be addressed: contrast- and signal-to-noise ratio, temporal and spatial resolution, and scan protocol.

Abstract

An interactive real-time imaging system capable of rapid coronary artery imaging is described. High-resolution spiral and circular echo planar trajectories were used to achieve 0.8 x 1.6 mm2 resolution in 135 ms (CEPI) or 1.13 x 1.13 mm2 resolution in 189 ms (spirals), over a 20-cm FOV. Using a sliding window reconstruction, display rates of up to 37 images/sec were achieved. Initial results indicate this technique can perform as a high-quality 2D coronary localizer and with SNR improvement may enable rapid screening of the coronary tree.

Abstract

We conducted an initial clinical trial of a newly developed cardiac magnetic resonance imaging (CMRI) system. We evaluated left ventricular (LV) function in 85 patients to compare the clinical utility of the CMRI system with echocardiography, the current noninvasive gold standard.Conventional CMRI systems require cardiac-gating and respiratory compensation to synthesize a single image from data acquired over multiple cardiac cycles. In contrast, the new CMRI system allows continuous real-time dynamic acquisition and display of any scan plane at 16 images/s without the need for cardiac gating or breath-holding.A conventional 1.5T Signa MRI Scanner (GE, Milwaukee, Wisconsin) was modified by the addition of an interactive workstation and a bus adapter. The new CMRI system underwent clinical trial by testing its ability to evaluate global and regional LV function. The first group (A) consisted of 31 patients with acceptable echocardiography image quality. The second group (B) consisted of 31 patients with suboptimal echocardiography image quality. The third group (C) consisted of 29 patients with severe lung disease or congenital cardiac malformation who frequently have suboptimal echo study. Two independent observers scored wall motion and image quality using the standard 16-segment model and rank-order analysis.CMRI evaluation was complete in less than 15 min. In group A, no significant difference was found between ECHO and CMRI studies (p = NS). In group B, adequate visualization of wall segments was obtained 38% of the time using ECHO and 97% of the time using CMRI (p < 0.0001). When grouped into coronary segments, adequate visualization of at least one segment occurred in 18 of 30 patients (60%) with ECHO and in all 30 patients (100%) with CMRI (p < 0.0001). In group C, adequate visualization of the wall segments was obtained in 58% (CI 0.53-0.62) of the time using echocardiography and 99.7% (CI 0.99-1.0) of the time using CMRI (p < 0.0001).The new CMRI system provides clinically reliable evaluation of LV function and complements suboptimal echocardiography. In comparison with the conventional CMRI, the new CMRI system significantly reduces scan time, patient discomfort and associated cost.